Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation

Brief Title

Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation

Official Title

A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of Zanubrutinib (BGB-3111), a BTK Inhibitor, Plus Tislelizumab (BGB-A317), a PD1 Inhibitor, for Treatment of Patients With Richter Transformation

Brief Summary

      The aim of the CLL-RT1 trial is to evaluate the efficacy and safety of zanubrutinib
      (BGB-3111), a BTK inhibitor plus tislelizumab (BGB-A317), a PD1 inhibitor for treatment of
      patients with Richter Transformation
    

Detailed Description

      Richter Transformation (RT) remains one of the biggest challenges in the treatment and
      management of CLL. While considerable progress has been made in the treatment of CLL, the
      prognosis of CLL patients with malignant disease transformation still is very poor and
      reported median OS is between 6 to 8 months. Conventional approaches with chemo- and
      chemoimmunotherapy have largely failed to improve response rates in RT patients. However, as
      the established treatment approach for de-novo Diffuse Large B Cell Lymphoma (DLBCL) is
      chemoimmunotherapy with a combination of Rituximab, Cyclophosphamid, Hydroxydaunorubicin,
      Vincristin and Prednisolon (R-CHOP), this has become the most commonly used regimen for lack
      of alternative strategies, despite poor efficacy. Patients being fit enough for allogeneic
      transplantation are undergoing this procedure after induction with R-CHOP. However, the
      majority of patients are not suitable for transplantation and relapse quickly. Hence, there
      is urgent need to improve therapy of RT by testing new compounds and combinations for
      treatment of this disease. Based on the available preclinical and preliminary clinical data
      on checkpoint inhibition plus Bruton's tyrosine (BTK) inhibition, the current trial will
      systematically assess the safety and toxicity of tislelizumab, a programmed cell death
      protein 1 (PD-1) inhibitor, plus zanubrutinib, a BTK inhibitor in patients with RT.
    

Study Phase

Phase 2

Study Type

Interventional

Primary Outcome

Overall response rate (ORR) after induction therapy according to the refined Lugano Classification (Cheson et al, 2016)

Secondary Outcome

 ORR after induction therapy according to the IWCLL criteria (Hallek et al, 2018)

Condition

Richter Transformation

Intervention

Tislelizumab

Study Arms / Comparison Groups

 Tislelizumab + Zanubrutinib

Description:  Induction: 6 cycles (q21d) of Tislelizumab + Zanubrutinib
Consolidation: 6 cycles (q21d) of Tislelizumab + Zanubrutinib
Maintenance: Patients with response to therapy continue to take Tislelizumab + Zanubrutinib (Q3W) until disease progression, non-tolerance or when receiving allogeneic stem cell transplantation (SCT) for consolidation

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Biological

Estimated Enrollment

48

Start Date

February 19, 2020

Completion Date

June 2023

Primary Completion Date

August 2022

Eligibility Criteria

        Inclusion Criteria:

          1. Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018)

          2. Confirmed histopathological diagnosis of RT

          3. Creatinine clearance ≥30ml/min calculated according to the modified formula of
             Cockcroft and Gault or directly measured with 24hr urine collection

          4. Adequate liver function as indicated by a total bilirubin ≤ 2x, AST/ALT ≤ 2.5 x the
             institutional ULN value, unless directly attributable to the patient's CLL/RT or to
             Gilbert's Syndrome, in which case a max. total bilirubin ≤ 4 x and AST/ALT ≤ 5 x the
             institutional ULN value are required

          5. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative;
             patients positive for anti-HBc may be included if PCR for HBV DNA is negative and
             HBV-DNA PCR is performed every two months until 2 months after last dose of
             zanubrutinib), negative testing for hepatitis-C RNA and negative HIV test within 6
             weeks prior to registration

          6. Age at least 18 years

          7. ECOG performance status 0-2, ECOG 3 is only permitted if related to CLL or RT (e.g.
             due to anaemia or severe constitutional symptoms)

          8. Life expectancy ≥ 6 months

          9. Ability and willingness to provide written informed consent and to adhere to the study
             visit schedule and other protocol requirements

        Exclusion Criteria:

          1. Patients who did not respond to previous line of RT therapy (i.e. primary progressive
             patients)

          2. Patients with more than one prior line of RT therapy

          3. Allogenic stem cell transplantation within the last 100 days or signs of active
             graft-versus-host disease (GVHD) after prior allogeneic stem cell transplantation
             within any time

          4. Patients with confirmed progressive multifocal leukoencephalopathy (PML)

          5. Uncontrolled autoimmune condition

          6. Malignancies other than CLL currently requiring systemic therapies

          7. Active infection currently requiring systemic treatment

          8. Any comorbidity or organ system impairment rated with a Cumulative Illness Rating
             Scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system, or
             any other life-threatening illness, medical condition or organ system dysfunction that
             - in the investigator´s opinion could comprise the patients safety or interfere with
             the absorption or metabolism of the study drugs

          9. Requirement of therapy with strong CYP3A4 inhibitors/inducers

         10. Requirement of therapy with phenprocoumon or other vitamin K antagonists.

         11. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs
             within clinical trials, which might interfere with the study drug within 28 days (or 5
             times half-life [t1/2] of the compound, whichever is longer) prior to registration

         12. Known hypersensitivity to tislelizumab, zanubrutinib or any of the excipients

         13. Pregnant women and nursing mothers (a negative pregnancy test is required for all
             women of childbearing potential within 7 days before start of treatment)

         14. Fertile men or women of childbearing potential unless:

               -  surgically sterile or ≥ 2 years after the onset of menopause, or

               -  willing to use two methods of reliable contraception including one highly
                  effective contraceptive method (Pearl Index <1) and one additional effective
                  (barrier) method during study treatment and for 12 months after the end of study
                  treatment.

         15. Vaccination with a live vaccine <28 days prior to randomization

         16. Legal incapacity

         17. Prisoners or subjects who are institutionalized by regulatory or court order

         18. Persons who are in dependence to the sponsor or an investigator
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Barbara Eichhorst, Prof., +4922147888220, [email protected]

Location Countries

Austria

Location Countries

Austria

NCT ID

NCT04271956

Organization ID

CLL-RT1

Responsible Party

Sponsor

Study Sponsor

German CLL Study Group

Study Sponsor

Barbara Eichhorst, Prof., Principal Investigator, Department I of Internal Medicine, University Hospital Cologne

Verification Date

March 2022